Abstract
Although most research to date on Trace Amine Associated Receptor 1 (TAAR1) has focused on its role in the brain, it has been recognized since its discovery in 2001 that TAAR1 mRNA is expressed in peripheral tissues as well, suggesting that this receptor may play a role in non-neurological pathways. This study reports TAAR1 expression, signaling and functionality in rhesus monkey lymphocytes. We detected a high level of TAAR1 protein in immortalized rhesus monkey B cell lines and a significant upregulation of TAAR1 protein expression in rhesus monkey lymphocytes following PHA treatment. Through screening a wide range of signaling pathways for their upregulation following TAAR1 activation by its potent agonist methamphetamine, we identified two transcription factors, CREB and NFAT, which are commonly associated with immune activation. Furthermore, we observed a TAAR1-dependent phosphorylation of PKA and PKC following treatment with methamphetamine in transfected HEK293 cells, immortalized rhesus monkey B cells and PHA-activated rhesus monkey lymphocytes. Accordingly, the high levels of TAAR1 that we observed on lymphocytes are inducible and fully functional, capable of transmitting a signal likely via PKA and PKC activation following ligand binding. More importantly, an increase in TAAR1 receptor expression is concomitant with lymphocyte immune activation, suggesting a possible role for TAAR1 in the generation or regulation of an immune response. TAAR1 is emerging as a potential therapeutic target, with regard to its ability to modulate brain monoamines. The current data raises the possibility that TAAR1-targeted drugs may also alter immune function.
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Blois JT, Mataraza JM, Mecklenbrauker I, Tarakhovsky A, Chiles TC (2004) B cell receptor-induced cAMP-response element-binding protein activation in B lymphocytes requires novel protein kinase Cdelta. J Biol Chem 279:30123–30132
Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C (2001) Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci USA 98:8966–8971
Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC, Bettler B (2009) The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci USA 106:20081–20086
Donnadieu E, Cefai D, Tan YP, Paresys G, Bismuth G, Trautmann A (1992) Imaging early steps of human T cell activation by antigen-presenting cells. J Immunol 148:2643–2653
Majumdar G, Beachey EH, Tomai M, Kotb M (1990) Differential signal requirements in T-cell activation by mitogen and superantigen. Cell Signal 2:521–530
Martin HJ, Lee JM, Walls D, Hayward SD (2007) Manipulation of the toll-like receptor 7 signaling pathway by Epstein-Barr virus. J Virol 81:9748–9758
Martinez LR, Mihu MR, Gacser A, Santambrogio L, Nosanchuk JD (2009) Methamphetamine enhances histoplasmosis by immunosuppression of the host. J Infect Dis 200:131–141
Miller GM (2011) The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem 116:164–176
Miller GM, Verrico CD, Jassen A, Konar M, Yang H, Panas H, Bahn M, Johnson R, Madras BK (2005) Primate trace amine receptor 1 modulation by the dopamine transporter. J Pharmacol Exp Ther 313:983–994
Nelson DA, Tolbert MD, Singh SJ, Bost KL (2007) Expression of neuronal trace amine-associated receptor (Taar) mRNAs in leukocytes. J Neuroimmunol 192:21–30
O’Donovan MR, Johns S, Wilcox P (1995) The effect of PHA stimulation on lymphocyte sub-populations in whole-blood cultures. Mutagenesis 10:371–374
Potula R, Hawkins BJ, Cenna JM, Fan S, Dykstra H, Ramirez SH, Morsey B, Brodie MR, Persidsky Y (2010) Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment. J Immunol 185:2867–2876
Samanta M, Iwakiri D, Kanda T, Imaizumi T, Takada K (2006) EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN. EMBO J 25:4207–4214
Verheugen JA, Le Deist F, Devignot V, Korn H (1997) Enhancement of calcium signaling and proliferation responses in activated human T lymphocytes. Inhibitory effects of K+ channel block by charybdotoxin depend on the T cell activation state. Cell Calcium 21:1–17
Wey SP, Wu HY, Chang FC, Jan TR (2008) Methamphetamine and diazepam suppress antigen-specific cytokine expression and antibody production in ovalbumin-sensitized BALB/c mice. Toxicol Lett 181:157–162
Xie Z, Miller GM (2007) Trace amine-associated receptor 1 is a modulator of the dopamine transporter. J Pharmacol Exp Ther 321:128–136
Xie Z, Miller GM (2008) Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain. J Pharmacol Exp Ther 325:617–628
Xie Z, Miller GM (2009) A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain. J Pharmacol Exp Ther 330:316–325
Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, Yao WD, Madras BK, Miller GM (2007) Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro. J Pharmacol Exp Ther 321:116–127
Xie Z, Westmoreland SV, Miller GM (2008) Modulation of monoamine transporters by common biogenic amines via trace amine-associated receptor 1 and monoamine autoreceptors in human embryonic kidney 293 cells and brain synaptosomes. J Pharmacol Exp Ther 325:629–640
Acknowledgments
We thank the New England Primate Research Center Primate Genetics Core for assistance in the production of immortalized B cell lines.
Support: DA030177 (GMM), DA025697 (GMM), RR00168 (NEPRC).
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The authors declare that they have no conflict of interest.
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Panas, M.W., Xie, Z., Panas, H.N. et al. Trace Amine Associated Receptor 1 Signaling in Activated Lymphocytes. J Neuroimmune Pharmacol 7, 866–876 (2012). https://doi.org/10.1007/s11481-011-9321-4
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DOI: https://doi.org/10.1007/s11481-011-9321-4